Pde4 inhibitors for the treatment of neoplasms of lymphoid cells

ABSTRACT

The invention relates to the use of certain PDE4 inhibitors alone or in combination with one or more differentiation inducing agents and/or an agent effective in raising intracellular concentrations of cAMP or a stable analogue of cAMP in the preparation of pharmaceutical compositions for the treatment of neoplasms of lymphoid cells.

FIELD OF APPLICATION OF THE INVENTION

The present invention relates to the use of certain PDE4 inhibitors inthe treatment of neoplasms of lymphoid cells.

KNOWN TECHNICAL BACKGROUND

Neoplasms of lymphoid cells can present clinically as leukemia, lymphomaand myeloma.

Leukemias are classified as either lymphocytic or myeloid, depending onthe type of leukocyte affected. In addition, leukemias are classified aseither acute, referring to a rapidly progressing disease that involvesimmature leukocytes, or chronic, referring to a slower proliferationinvolving mature white cells. In acute leukemias, immaturenonfunctioning leukocytes called blast cells proliferate.

The myeloid leukemias affect white blood cells (myelocytes) that giverise to granulocytes (phagocytic white blood cells that mount aninflammatory immune response). They include chronic myeloid leukemia(CML) and acute myeloid leukemia (AML), also called acute nonlymphocyticleukemia (ANLL).

The lymphocytic leukemias affect the white blood cells that give rise tovarious types of lymphocytes. They include acute lymphocytic leukemia(ALL); chronic lymphocytic leukemia (CLL), also called chronicgranulocytic leukemia; and hairy cell leukemia (HCL), a chronic leukemianamed for the cells' tiny hairlike projections. The lymphocyticleukemias are sometimes referred to as B cell leukemias or T cellleukemias depending upon whether they arise in antibody-producing Bcells (HCL, CLL, and some cases of ALL) or in the T cell lymphocytesinvolved in cell-mediated immunity (some cases of ALL). Each of thesetypes may be further classified into subtypes. Most childhood leukemiasare of the acute lymphocytic type, acute myeloid leukemia is the mostcommon type of adult leukemia.

The diagnosis of leukemia is confirmed by finding a disproportionatenumber of leukocytes in tissue obtained from a bone marrow biopsy. Thecourse of treatment is based upon the type of cell affected, theprogression of the disease, and the age of the patient.

Treatment may include chemotherapy with anticancer drugs, radiationtherapy, blood and plasma transfusions, and bone marrow transplantation.In bone marrow transplantation, healthy bone marrow (either donated by aclosely matched donor or treated marrow from the patent) is infused intothe patient after the patient has undergone a course ofmarrow-destroying very high dose chemotherapy.

Recent studies have indicated that blood from a newborn infant'sumbilical cord and placenta (called cord blood) can be used effectivelyinstead of marrow transplants in some leukemias. Biological therapy(sometimes called immunotherapy) is also being introduced. Biologicaltherapies include monoclonal antibodies, interferons, and maturationdrugs, such as all-trans retinoic acid. These therapies may enhance thebody's natural reaction to leukemia by bolstering the immune response ormay encourage maturation of immature leukemic cells or reproduction ofneeded healthy blood elements.

Another more experimental approach suggests that agents capable ofmodulating 3′,5′-cyclic adenosine monophosphate (cAMP) levels might beuseful for the treatment of lymphoid malignancies (Lerner A, Kim B, LeeR. Leuk Lymphoma 2000; 37:39-51). It has been published that elevatedintracellular levels of cAMP can induce apoptosis in susceptiblesubpopulations of both B- and T-lineage lymphocytes. One means ofaugmenting cAMP signaling has been through the use of cAMPphosphodiesterase (PDE) inhibitors, as inhibition of cAMP catabolismresults in elevation of intracellular lymphoid cAMP levels in vivo(Tohda Y, Nakahara H, Kubo H, Ohkawa K, Fukuoka M, Nakajima S. Gen.Pharmacol. 1998; 31: 409-13). Theophylline, a nonspecific methylxanthinePDE inhibitor, has been shown to induce apoptosis in chronic lymphocyticleukemia (CLL) B-lymphocytes in vitro (Mentz F, Merle-Beral H, Ouaaz F,Binet J-L. Br. J. Hematol. 1995; 90: 957-9; Mentz F, Mossalayi M D,Ouaaz F, Baudet S, Issaly F, Ktorza S, Semichon M, Binet J-L,Merle-Beral H. Blood 1996; 88: 2172-82). A subsequent Phase 2 clinicaltrial demonstrated that combined treatment with theophylline andchlorambucil induced positive responses in CLL patents who failedtreatment with chlorambucil alone (Binet J-L, Mentz F, Leblond V,Merle-Beral H. Leukemia 1995; 9: 2159). Since theophylline is anonselective PDE inhibitor as well as an adenosine receptor antagonist,this reagent complicates both the clinical and research applications. Amore selective PDE inhibitor might also induce apoptosis in lymphoidcells and have therapeutic value in the treatment of lymphoidmalignancies. Lymphoid cells contain several classes of cyclicnucleotide PDEs, including cGMP-inhibited PDE3 (Ekholm D, Hemmer B, GaoG, Vergelli M, Martin R, Manganiello V. J. Immunol. 1997; 159:1520-9)and cAMP-specific PDE4 (Erdogan S, Houslay M D. Biochem. J. 1997;321:165-75).

Certain recently published scientific papers mention the potential useof PDE4 inhibitors in the induction of apoptosis in CLL cells (see forexample: Kim, D. H. and Lerner A: “Type 4 cyclic adenosine monophosphatephosphodiesterase as a therapeutic target in chronic lymphocyticleukemia”, Blood, 92: 2484-2494, 1998; Lerner A., Kim B. and Lee R.:“The cAMP signalling pathway as a therapeutic target in lymphoidmalignancies”. Leuk Lymphoma, 37: 39-51, 2000). In other publications itis de scribed that PDE4 inhibitors may also have therapeutic potentialin human acute lymphoblastic leukemia (see for example: R. Ogawa, M. B.Streiff, A. Bugayenko and G. J. Kato: “Inhibition of PDE4phosphodiesterase activity induces growth suppression, apoptosis,glucocorticoid sensitivity, p53 and p21^(WAF1/CIP1) proteins in humanacute lymphoblastic leukemia cells”).

DESCRIPTION OF THE INVENTION

It has been found that certain PDE4 inhibitors alone or in combinationwith differentiation inducing agents and/or cAMP agonists or stableanalogs of cAMP are particularly useful in the treatment of neoplasms oflymphoid cells.

One class of PDE4 inhibitor compounds that may be usefully employed inthe present invention includes compounds of formula 1 (embodiment A):

in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   A represents S (sulfur), S(O) (sulfoxide) or S(O)₂ (sulfone),-   Ar represents a benzene derivative of formula (a) or (b)    wherein-   R3 is halogen, 1-4C-alkoxy, or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R4 is halogen, 1-8C-alkoxy, 3-7C-cycloalkoxy,    3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R5 is halogen, 1-4C-alkoxy, 3-5C-cycloalkoxy,    3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or    predominantly substituted by fluorine,-   R6 is 1-4C-alkyl and-   R7 is hydrogen or 14C-alkyl,    or wherein-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked 5-, 6- or 7-membered    hydrocarbon ring, optionally interrupted by an oxygen or sulphur    atom,    or the pharmaceutically acceptable salts thereof.

Compounds of embodiment A which are to be emphasized in this connectionare those compounds of formula 1 in which

-   R1 and R2 together form an additional bond,-   A represents S(O) (sulfoxide) or S(O)₂ (sulfone),-   Ar represents a benzene derivative of formula (a) or (b)    wherein-   R3 is 1-2C-alkoxy, or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R4 is halogen, 1-4C-alkoxy or 3-5C-cycloalkoxy,-   R5 is 1-2C-alkoxy, or 1-2C-alkoxy which is completely or    predominantly substituted by fluorine,-   R6 is methyl,-   R7 is hydrogen,    or wherein-   R6 and R7 together and with inclusion of the two carbon atoms, to    which they are bonded, form a spiro-linked cyclopentane or    cyclohexane ring,    or the pharmaceutically acceptable salts thereof.

Preferred compounds of embodiment A are in this connection compounds offormula 1 selected from

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyranyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Dimethoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3-Chloro-4-methoxyphenyl)-2-(1-oxo-hexahydro-1l⁴-thiopyranyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(3,4-Diethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁸-thiopyranyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aR,8aS)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    and-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    or the pharmaceutically acceptable salts thereof.

Particularly preferred compounds of embodiment A in this connection arecompounds of formula 1 selected from

-   (cis)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-yl)-2-(tetrahydrothiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-(cis)-4-(3,4-Dimethoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyranyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    and-   (cis)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(1,1-dioxohexahydro-1l⁶-thiopyran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one    or the pharmaceutically acceptable salts thereof.

The preparation of the compounds of embodiment A as well as their use asPDE4 inhibitors is disclosed in the International Patent applicationWO01/30777.

Another class of PDE4 inhibitors that may be usefully employed in thepresent invention includes compounds of formula 2 (Embodiment B)

in which

-   R1 and R2 are both hydrogen or together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)    wherein    -   R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or        predominantly substituted by fluorine,    -   R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or        1-4C-alkoxy which is completely or predominantly substituted by        fluorine,    -   R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or        1-4C-alkoxy which is completely or predominantly substituted by        fluorine,    -   R7 is 1-4AC-alkyl and    -   R8 is hydrogen or 1-4C-alkyl,    -   or wherein    -   R7 and R8 together and with inclusion of the two carbon atoms,        to which they are bonded, form a spiro-linked 5-, 6- or        7-membered hydrocarbon ring, optionally interrupted by an oxygen        or sulphur atom,-   R9 is 1-4C-alkyl, —S(O)₂—R10, —S(O)₂—(CH₂)_(n)—R11,    —(CH₂)_(m)—S(O)₂—R12, —C(O)R13, —C(O)—(CH₂)_(n)—R14,    —(CH₂)_(m)—C(O)—R15, Hetaryl, Aryl1 or 1-4C-alkyl-Aryl2,-   R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17,    phenyl or phenyl substituted by R18 and/or R19,-   R11 is —N(R16)R17,-   R12 is —N(R16)R17,-   R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl,    4-ethyl-piperazin-2,3-dion-1-yl or —N(R16)R17,-   R14 is —N(R16)R17,-   R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19    and/or R20,-   R16 and R17 are independent from each other hydrogen, 1-7C-alkyl,    3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, phenyl or phenyl substituted    by R18 and/or R19 and/or R20, or R16 and R17 together and with    inclusion of the nitrogen atom to which they are bonded, form a    4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino-    or a 1-piperazinyl-ring of formula (c)    -   wherein    -   R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyldimethylamino,        dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl,        4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,-   R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl,    1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino or mono-    or di-1-4C-alkylaminocarbonyl,-   R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,-   R20 is halogen,-   Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl,    1-methyl-1H-pyrazolo-[3,4d]pyrimidin-4-yl, thiazolyl, imidazolyl or    furanyl,-   Aryl1 is pyridyl, phenyl or phenyl substituted by R18 and/or R19,-   Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19,    2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl,-   n is an integer from 1 to 4,-   m is an integer from 1 to 4,    or the pharmaceutical acceptable salts thereof.

Compounds of embodiment B which are to be emphasized in this connectionare those compounds of formula 2 in which

-   R1 and R2 together form an additional bond,-   R3 represents a benzene derivative of formula (a) or (b)    wherein    -   R4 is methoxy or ethoxy,    -   R5 is methoxy or ethoxy,    -   R6 is methoxy or ethoxy,    -   R7 is methyl and    -   R8 is hydrogen,-   R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5-oxo-pentanoic    acid, pyridin-4-yl-carbonyl, tert-butylaminocarbonyl,    phenylaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl,    4-nitro-phenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl,    2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl,    1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,    thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl,    2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl,    phenethyl, pyridin-3-ylmethyl, pyridin-2-ylmethyl,    pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl,    2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl,    isopropylaminocarbonylmethyl,    4-ethyl-piperazine-2,3-dione-1-carbonyl,    4-(1,2,3-thiadiazol-4-yl-)benzyl,    4-ethoxycarbonylphenylamino-2-oxo-ethyl or aminocarbonyl-methyl,    or the pharmaceutical acceptable salts thereof.

Preferred compounds of embodiment B in this connection are compounds offormula 2 selected from

-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid phenylamide,-   4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholin-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxoethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4]pyrimidin-4-yl)piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]piperidin-1-yl}-N-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethylpiperazine-2,3-dione,-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)benzoic    acid ethyl ester and-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]piperidin-1-yl}-acetamide,    or the pharmaceutical acceptable salts thereof.

Further preferred compounds of embodiment B in this connection arecompounds of formula 2 selected from

-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluenesulfonyl)piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   5-{4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-5-oxo-pentanoic    acid,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]piperidine-1-carboxylic    acid phenylamide,-   (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic    acid tert-butylamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-2-{1-[2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   4-(3,4-Dimethoxyphenyl)-2-(1-isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,    (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-isopropyl-acetamide,-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

1-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,

-   4-(2-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic    acid ethyl ester and-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide,    or the pharmaceutically acceptable salts thereof.

Particularly preferred compounds of embodiment B in this connection arecompounds of formula 2 selected from

-   (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,-   2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide,    or the pharmaceutically acceptable salts thereof.

The preparation of the compounds of embodiment B as well as their use asPDE4 inhibitors is disclosed in the International Patent applicationWO02/064584.

Still another group of PDE4 inhibitors (embodiment C) that may beusefully employed in the present invention includes the followingcompounds:

-   -   N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy 4-methoxybenzamide        [INN: PICLAMILAST] and its salts; the preparation of this        compound and its pharmaceutically acceptable salts as well as        their use as PDE4 inhibitors is disclosed in the international        patent application WO92/12961    -   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide        [INN: ROFLUMILAST] and its salts; the preparation of this        compound and its pharmaceutically acceptable salts as well as        their use as PDE4 inhibitors is disclosed in the international        patent application WO95/01338    -   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyridyl)-benzamide        (Roflumilast-N-Oxide) and its salts; the preparation of this        compound and its pharmaceutically acceptable salts as well as        their use as PDE4 inhibitors is disclosed in the international        patent application WO95/01338    -   3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine        [Research Code: V-11294A]; the preparation of this compound and        its pharmaceutically acceptable salts as well as their use as        PDE4 inhibitors is disclosed in the international patent        application WO95/00516    -   N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide        [Research Code: CI-1018]; the preparation of this compound and        its pharmaceutically acceptable salts as well as their use as        PDE4 inhibitors is disclosed in the international patent        application WO96/11690.    -   3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN        AROFYLLINE]; the preparation of this compound and its        pharmaceutically acceptable salts as well as their use as PDE4        inhibitors is disclosed in the European patent application        EP0435811.    -   N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide        [Research Code: AWD-12-281]; the preparation of this compound        and its pharmaceutically acceptable salts as well as their use        as PDE4 inhibitors is disclosed in the international patent        application WO98/09946    -   N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indo-3-yl-2-oxoacetamide        [Research Code: AWD-12-343]; the preparation of this compound        and its pharmaceutically acceptable salts as well as their use        as PDE4 inhibitors is disclosed in the international patent        application WO98/09946.    -   Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone        [INN: ATIZORAM]; the preparation of this compound and its        pharmaceutically acceptable salts as well as their use as PDE4        inhibitors is disclosed in the European patent application        EP0389282.    -   β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide        [Research Code: CDC-801]; the preparation of this compound and        its pharmaceutically acceptable salts as well as their use as        PDE4 inhibitors is disclosed in the international patent        application WO97/23457.    -   Methanesulfonic acid        2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furanyl-6-yl ester        [INN: LIRIMILAST]; the preparation of this compound and its        pharmaceutically acceptable salts as well as their use as PDE4        inhibitors is disclosed in the European patent application        EP0731099.    -   3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide        (Research Code: SCH-351591]; the preparation of this compound        and its pharmaceutically acceptable salts as well as their use        as PDE4 inhibitors is disclosed in the international patent        application WO00/26208;    -   cis-4-cyan-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic        acid [INN: Cilomilast], the preparation of this compound and its        pharmaceutically acceptable salts as well as their use as PDE4        inhibitors is disclosed in the International patent application        WO93/19749        as well as the compounds with the research codes CDC-998, D4396,        IC-485, CC-1088 and KW4490 and their pharmaceutically acceptable        salts.

Preferred compounds of embodiment C are in this connection

-   N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide    [Research Code: AWD12-281],-   cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic    acid [INN: Cilomilast],-   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide    [INN: ROFLUMILAST],-   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide    (Roflumilast-N-Oxide) and their pharmaceutically acceptable salts.

Particularly preferred compounds of embodiment C are in this connection

-   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide    [INN: ROFLUMILAST],-   3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide    (Roflumilast-N-Oxide) and their pharmaceutically acceptable salts.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

1-4C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms, which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

1-8C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 8 carbon atoms.Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned inthis context are, for example, the octyloxy, heptyloxy, isoheptyloxy(5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

Halogen within the meaning of the present invention is bromine, chlorineor fluorine.

3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy andcyclopentyloxy.

3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxyand cyclopentylmethoxy.

1-4C-Alkoxy which is completely or predominantly substituted by fluorineis, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy,the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1-4C-alkoxy groupare replaced by fluorine atoms.

As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionallyinterrupted by an oxygen or sulphur atom, may be mentioned thecyclopentane, cyclohexane, cycloheptane, tetrahydrofuran,tetrahydropyran and the tetrahydrothiophen ring.

1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is the acetylradical [CH₃C(O)—].

An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino[C₃H₇C(O)NH—] and the acetylamino radical [CH₃C(O)NH—].

Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the abovementioned 1-4C-alkyl radicals. Preferredare the di-1-4C-alkylamino radicals, especially the dimethylamino, thediethylamino and the diisopropylamino radical.

Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to thecarbonyl group one of the abovementioned mono- or di-1-4C-alkylaminoradicals. Examples which may be mentioned are the N-methyl- theN,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and theN-isopropylaminocarbonyl radical.

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting a free base with a suitable organic orinorganic acid or by reacting the acid with a suitable organic orinorganic base. Particular mention may be made of the pharmaceuticallyacceptable inorganic and organic acids customarily used in pharmacy.Those suitable are water-soluble and water-insoluble acid addition saltswith acids such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyricacid, sulphosalicylic acid, maleic acid, lauric acid, malic acid,fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid,stearic acid, toluenesulphonic acid, methanesulphonic acid or3-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether a mono- or polybasic acid is concernedand depending on which salt is desired—in an equimolar quantitativeratio or one differing therefrom.

For the purposes of this invention the expression “neoplasms of lymphoidcells” includes leukemia, lymphoma and myeloma. More specifically itincludes the different types of leukemia, the myelodysplastic syndromesand lymphoma.

The expression “different types of leukemia” includes the myeloidleukemias CML (chronic myeloid leukemia), AML (acute myeloid leukemia)and ANLL (acute nonlymphocytic leukemia) as well as the lymphocyticleukemias ALL (acute lymphocytic leukemia), CLL (chronic lymphocyticleukemia) and HCL (hairy cell leukemia). AML can further besubclassified in acute promyelocytic leukemia (APL), acutemyelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemiaand acute megakaryocytic leukemia. APL is a rare form of acutemyelogenous leukemia with typical chromosomal translocations leading tothe expression of abnormal fusion proteins involving the nuclearretinoic acid receptor, RARα.

The myeloplastic syndromes (MDS) are heterogenous clonal hematopoieticstem cell disorders grouped together because of the presence ofdysplastic changes in one or more of the hematopoietic lineages. MDSwere previously referred to as smoldering leukemia or preleukeamia,oligoblastic leukemia or hematopoietic dysplasia, implying an indolentcourse.

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoidmalignancy in adults; it is curable only in less than 50% of patients.Lymphomas are typically subdivided into Hodkin's- and non-Hodkin'slymphoma.

In a first aspect of the present invention, there is provided the use ofa compound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C in the preparation of apharmaceutical composition for the treatment of neoplasms of lymphoidcells.

In a second aspect of the present invention there is provided a methodof treating neoplasms of lymphoid cells in a mammal includingadministering to the mammal a therapeutically effective amount of acompound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C.

In a third aspect of the present invention, there is provided atreatment combination for neoplasms of lymphoid cells, including:therapeutically effective amounts of (i) a compound (compound to beemphasized, preferred compound, particularly preferred compound) ofembodiment A, B or C; and (ii) one or more differentiation inducingagents and/or an agent effective in raising intracellular concentrationsof cAMP or a stable analogue of cAMP.

In a forth aspect of the present invention, there is provided atreatment combination for neoplasms of lymphoid cells, including:therapeutically effective amounts of (i) a compound (compound to beemphasized, preferred compound, particularly preferred compound) ofembodiment A, B or C; and (ii) one or more differentiation inducingagents.

In a fifth aspect of the present invention, there is provided atreatment combination for neoplasms of lymphoid cells, including:therapeutically effective amounts of (i) a compound (compound to beemphasized, preferred compound, particularly preferred compound) ofembodiment A, B or C; and (ii) an agent effective in raisingintracellular concentrations of cAMP or a stable analogue of cAMP.

In a sixth aspect of the present invention, there is provided the use ofa compound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C and one or moredifferentiation inducing agents and/or an agent effective in raisingintracellular concentrations of cAMP or a stable analogue of cAMP in thepreparation of a pharmaceutical composition for the treatment ofneoplasms of lymphoid cells.

In a seventh aspect of the present invention, there is provided the useof a compound (compound to be emphasized, preferred compound,particularly preferred compound) of embodiment A, B or C and one or moredifferentiation inducing agents in the preparation of a pharmaceuticalcomposition for the treatment of neoplasms of lymphoid cells.

In a eighth aspect of the present invention, there is provided the useof a compound (compound to be emphasized, preferred compound,particularly preferred compound) of embodiment A, B or C and an agenteffective in raising intracellular concentrations of cAMP or a stableanalogue of cAMP in the preparation of a pharmaceutical composition forthe treatment of neoplasms of lymphoid cells.

In a ninth aspect of the present invention, there is provided a methodof treating neoplasms of lymphoid cells in a mammal, including:administering to said mammal therapeutically effective amounts of (i) acompound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C; and (ii) one or moredifferentiation inducing agents and/or an agent effective in raisingintracellular concentrations of cAMP or a stable analogue of cAMP.

In a tenth aspect of the present invention, there is provided a methodof treating neoplasms of lymphoid cells in a mammal, including:administering to said mammal therapeutically effective amounts of (i) acompound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C; and (ii) one or moredifferentiation inducing agents.

In a twelfth aspect of the present invention, there is provided a methodof treating neoplasms of lymphoid cells in a mammal, including:administering to said mammal therapeutically effective amounts of (i) acompound (compound to be emphasized, preferred compound, particularlypreferred compound) of embodiment A, B or C; and (ii) an agent effectivein raising intracellular concentrations of cAMP or a stable analogue ofcAMP.

As recited above, in one aspect of the present invention a method oftreating neoplasms of lymphoid cells is provided, which includesadministering therapeutically effective amounts of (i) a compound ofembodiment A, B or C; and (ii) one or more differentiation inducingagents and/or an agent effective in raising intracellular concentrationsof cAMP or a stable analogue of cAMP.

Typical differentiation inducing agents useful in the present inventioninclude, but are not limited to, ATRA (all trans retinoic acid),13-cis-retinoic acid, CD437[6-(3-(1-adamantyl)-4-hydroxyphenyl)-2-naphthalene carboxylic acid],rexinoids (e.g. LG1069, LG100268, bexarotene, CD2809), HDAC inhibitors[histone deacetylase inhibitors, e.g.N-[4-[N-(2-aminophenyl)carbamoyl]benzyl]carbamic acid 3-pyridylmethylester (Research Code: MS-27-275, EP 0847992);N-hydroxy-N′-phenyloctanediamide (Research Code: SAHA; WO93/07148);4-acetamido-N-(2-aminophenyl)benzamide (Research Code: PD-123654; EP0242851); butanoic acid pivaloyloxymethyl ester (Research Code: AN-9;EP0302349); N′-hydroxy-N-(3-pyridyl)octane-1,8-dicarboxamide (INN:PYROXAMIDE);3-[4-[N-(2-hydroxyethyl)-N-[2-(1H-indol-3-yl)ethyl]aminomethyl]phenyl]-2-propenohydroxamicacid (INN: DACINOSTAT; WO02/22577);N-[5-(N-hydroxycarbamoyl)pentyl]indane-2-carboxamide (Research Code:PX-117735; WO02/30879);6-[2-(9H-fluoren-9-ylidene)acetamido]hexanohydroxamic acid (ResearchCode: PX-117456; WO02/26696);N-[5-(N-hydroxycarbamoyl)pentyl]naphthalene-2-carboxamide (ResearchCode: PX-117445; WO02/30879)], DNA methyltransferase inhibitors (e.g.5-azacytidine), hematopoietic growth factors (e.g. G-CSF, GM-CSF),interferon α, interleukin 1, TRAIL, HMBA (hexamethylene bisacetamide),vitamin D3 and analogs (e.g. cholecalciferol), arsenic trioxide(Trisenox, Cell Therapeutics, Inc. Seattle, Wash.), EGCG (green teacatechin epigallocatechin-3-gallate), DNA topoisomerase II inhibitors(e.g. ICRF-154, ICRF-193, etoposide), taraxinic acid, verticinone,PPAR-gamma agonists (e.g. thiazolidinediones (TZDs), troglitazone),antibodies versus CD19, CD20 (rituximab), CD22 or CD52 (alemtuzumab),CD33-antibodies alone or as conjugate [e.g. mylotarg(CD33-calicheamicin)], alkylating cytostatika (e.g. cyclphosphamide,chlorambucil), purine analogs (thioguanine, fludarabine),cytosine-arabinosides (e.g. AraC), anticyclines (e.g. daunorubicine),vinca-alkaloids (e.g. vincristine) and glucocorticosteroids. Preferredare in this connection the histone deacetylase inhibitors and the alltrans retinoic acid. Particularly preferred is the all trans retinoicacid.

As suitable agents effective in raising intracellular concentrations ofcAMP may be mentioned agents which (1) increase cAMP levels byactivating cell surface receptors which are Gs protein coupled to thecAMP generating enzyme adenylyl cyclase including, but not limited to,prostaglandin E2, prostacyclin derivatives (e.g. iloprost), dopamine,dobutamine, β2-adrenoreceptor agonists (for example: terbutaline,albuterol, pirbuterol, bitolterol, formoterol, salmeterol andsalbutamol), adenosine A1 receptor agonists, and adenosine A2 receptoragonists; and (2) increase cAMP levels by directly stimulating adenylylcyclase, including, but not limited to forskolin.

As examples of stable analogs of cAMP may be mentioned dibutyryl cAMP,8-chloro-cAMP and 8-bromo cAMP.

The invention relates to several methods for the treatment of mammals,which are suffering from neoplasms of lymphoid cells. The term mammalincludes the meaning human being.

The compound of embodiment A, B and C, the differentiation inducingagent(s) and/or the agent effective in raising intracellularconcentrations of cAMP or the stable analogue of cAMP may be employed incombination in accordance with the invention by administrationconcomitantly in (1) a unitary pharmaceutical composition including both(or all three) active compounds or (2) in separate pharmaceuticalcompositions each including one of the active compounds. Alternatively,the active compounds of the combination may be administered separatelyin a sequential manner wherein the compound of embodiment A, B or C, thedifferentiation inducing agent(s), the agent effective in raisingintracellular concentrations of cAMP or the stable analogue of cAMP isadministered first and the other(s) second. Such sequentialadministration may be close in time or remote in time.

The compound of embodiment A, B or C, the differentiation inducingagent(s), the agents which are effective to raise intracellular cAMPconcentrations and the stable analogs of cAMP of the present inventionmay be administered by any appropriate route. Suitable routes includeoral, rectal, nasal, topical, parenteral (including subcutaneous,intramuscular, intravenous and intradermal) and by inhalation.

The treatment combinations and pharmaceutical compositions are preparedby processes, which are known per se and familiar to the person skilledin the art As treatment combinations or pharmaceutical compositions, thecompounds the different compounds according to the invention (=activecompounds) are either employed as such, or preferably in combinationwith suitable pharmaceutical auxiliaries and/or excipients, e.g. in theform of tablets, coated tablets, capsules, caplets, suppositories,patches (e.g. as TTS), emulsions, suspensions, aerosols, gels orsolutions, the active compound(s) content advantageously being between0.1 and 95% and where, by appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or a enteric form) exactly suited to the active compound(s) and/orthe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries orexcipients, which are suitable for the desired pharmaceuticalformulations on account of his/her expert knowledge. In addition tosolvents, gel formers, ointment bases other active compound excipients,for example antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents, or permeation promoters canbe used.

As indicated, therapeutically effective amounts of the certain PDE4inhibitors, and if utilized, the differentiation inducing agent(s)and/or the agent, that is effective to raise intracellular cAMPconcentrations or the stable analogue of cAMP, are administered to themammal.

It is known to the person skilled in the art that the optimal dose ofan/the active compound(s) can vary as a function of the body weight, theage and the general condition of the patient, and his/her responsebehaviour to the active compound(s).

The customary dose of the PDE4 inhibitor compounds of embodiment A, B orC in the case of systemic therapy (p.o. or i.v.) is between 0.001 and 3mg/kg body weight of recipient (mammal) per day.

In case of oral administration of3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide (ROFLUMILAST), the adult daily dose is in the range from50-1000 μg, preferably in the range from 250-500 μg, preferably by oncedaily administration.

The daily dosage of the differentiation inducing agent all transretinoic acid (ATRA) is between 0.1 and 30 mg/kg body weight ofrecipient (mammal), and preferably from about 0.2 to about 5 mg/kg bodyweight of recipient (mammal). The daily dosage of the other indicateddifferentiation inducing agents may be from about 0.001 to about 100mg/kg body weight of recipient, depending on the employeddifferentiation inducing agent.

The daily dosages of the agent, which is effective to raiseintracellular cAMP concentrations may be from about 0.001 to about 15mg/kg body weight of recipient (mammal).

Pharmacology

It was demonstrated in a study thatN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST], a selective phosphodiesterase 4 (PDE4) inhibitor,potentiates the growth inhibitory and cyto-differentiating activities ofall trans retinoic acid (ATRA) in NB4, HL-60 and U937 blasts, whichrepresent in vitro models of ATRA induced granulocytic maturation ofacute myelogenous leukemia (AML). In NB4 cells, PICLAMILAST acceleratesthe process of morphological granulocytic maturation and enhances theATRA-dependent induction of specific differentiation markers such asNBT-reductase (NBTR) as well as CD11b. PICLAMILAST not only enhances,but also accelerates the process of granulocytic maturation set inmotion by ATRA in acute myelogenous leukemia cells, reducing the timenecessary to expose cells to ATRA to obtain maximal differentiation.Moreover, the compound increases the growth inhibitory effect of theretinoid in an additive fashion. PICLAMILAST treatment of NB4 cellsresults in a significant increase in the amounts of intracellular cAMPand cAMP-dependent protein kinase (PKA) over what observed in basalconditions. Neither basal nor PICLAMILAST-induced levels of cAMP and PKAare modulated by ATRA. PICLAMILAST exerts differential effects on anumber of transcriptional factors involved in the process of leukemiccell maturation triggered by ATRA. In combination with the retinoid: I)it enhances the ligand-dependent transcriptional activity of theretinoic acid receptor, RARalpha, but not that of PML-RARalpha, theabnormal fusion product selectively expressed in acute promyelocyticleukemia blasts and NB4 cells. The phenomenon is associated with aPKA-dependent phosphorylation of RARalpha, which is activated by thePDE4 inhibitor, II) it causes an increase in the amounts of cEBPalpha aswell as in the amounts and the activation state (tyrosinephosphorylation) of STAT1; III) it has no significant effect on theupregulation of cEBPepsilon. The direct modulation of RARalpha mayunderlie the enhancing action of PICLAMILAST on the expression ofnumerous ATRA-dependent genes, including cathepsin D and syaloadhesin.The PICLAMILAST dependent enhancement of the ATRA-dependent induction ofNBT-R is suppressed by the cAMP antagonist, Rp-8Br-cAMP, and thespecific PKA inhibitor H-89. However, H89 does not have the same effecton all the ATRA-dependent genes whose expression is super-induced by thePDE4 inhibitor. This indicates that PKA is not a necessary mediator ofthe interaction between PICLAMILAST and ATRA in myeloid cells.Surprisingly, treatment with PICLAMILAST results in a down-regulatoryaction on the phosphorylation state of the cAMP dependent CREBPtranscriptional factor, which is highly active in undifferentiated NB4cells. This phenomenon is more evident when cells are treated withcombinations of ATRA and the PDE4 inhibitor. Interestingly, in NB4cells, PICLAMILAST does not modulate the expression of cAMP- andCREBP-dependent genes, such as vinculin. Most importantly, thecombination of PICLAMILAST+ATRA is more effective than the singlecomponents on the survival of SCID mice transplanted with NB4 cells.This altogether could represent a clinically relevant finding as it mayrepresent a useful strategy to increase the therapeutic index of ATRA bydecreasing its local and systemic toxicity.

1.-38. (canceled)
 39. A method of treating neoplasms of lymphoid cellsin a mammal, comprising administering to said mammal a therapeuticallyeffective amount of a compound selected from the group consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018),3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490, and pharmaceutically acceptable saltsthereof.
 40. A method for treating neoplasms of lymphoid cells in amammal, comprising administering to said mammal therapeuticallyeffective amounts of (i) a compound selected from the group consistingof N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490, and pharmaceutically acceptable saltsthereof, and (ii) one or more differentiation inducing agents and/or anagent effective in raising intracellular concentrations of cAMP or astable analogue thereof.
 41. A method for treating neoplasms of lymphoidcells in a mammal, comprising administering to said mammaltherapeutically effective amounts of (i) a compound selected from thegroup consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490, and pharmaceutically acceptable saltsthereof, and (ii) one or more differentiation inducing agents.
 42. Amethod for treating neoplasms of lymphoid cells in a mammal, comprisingadministering to said mammal therapeutically effective amounts of (i) acompound selected from the group consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490, and pharmaceutically acceptable saltsthereof, and (ii) an agent effective in raising intracellularconcentrations of cAMP or a stable analogue thereof.
 43. (canceled) 44.The method according to claim 39, wherein the compound of component (i)is selected from the group consisting ofN-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof. 45.The method according to claim 39, wherein the compound of component (i)is selected from the group consisting of3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof. 46.The method according to claim 39, wherein the compound of component (i)is3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt thereof. 47.The method according to claim 39, wherein the compound of component (i)is3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) or a pharmaceutically acceptable salt thereof. 48.The method according to claim 39, wherein the compound of component (i)isN-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281] or a pharmaceutically acceptable saltthereof.
 49. The method according to claim 39, wherein the compound ofcomponent (i) iscis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast] or a pharmaceutically acceptable salt thereof.50.-61. (canceled)
 62. A treatment combination for neoplasms of lymphoidcells, comprising: therapeutically effective amounts of (i) a compoundselected from the group consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490 and pharmaceutically acceptable saltsthereof, and (ii) one or more differentiation inducing agents and/or anagent effective in raising intracellular concentrations of cAMP or astable analogue of cAMP.
 63. A treatment combination for neoplasms oflymphoid cells, comprising: therapeutically effective amounts of (i) acompound selected from the group consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490 and pharmaceutically acceptable saltsthereof, and (ii) one or more differentiation inducing agents.
 64. Atreatment combination for neoplasms of lymphoid cells, comprising:therapeutically effective amounts of (i) a compound selected from thegroup consisting ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN:PICLAMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide),3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM];β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide[Research Code: SCH-351591],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast], a compound with the research code CDC-998,D-4396, IC-485, CC-1088 or KW4490 and pharmaceutically acceptable saltsthereof, and (ii) an agent effective in raising intracellularconcentrations of cAMP or a stable analogue of cAMP.
 65. The treatmentcombination according to claim 62, wherein the compound of component (i)is selected from the group consisting ofN-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof. 66.The treatment combination according to claim 62, wherein the compound ofcomponent (i) is selected from the group consisting of3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide(INN: ROFLUMILAST],3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof. 67.The treatment combination according to claim 62, wherein the compound ofcomponent (i) is3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt thereof. 68.The treatment combination according to claim 62, wherein the compound ofcomponent (i) is3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide(Roflumilast-N-Oxide) or a pharmaceutically acceptable salt thereof. 69.The treatment combination according to claim 62, wherein the compound ofcomponent (i) isN-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281] or a pharmaceutically acceptable saltthereof.
 70. The treatment combination according to claim 62, whereinthe compound of component (i) iscis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylicacid [INN: Cilomilast] or a pharmaceutically acceptable salt thereof.71.-74. (canceled)
 75. The method according to claim 40, wherein thedifferentiation inducing agent is selected from the group consisting ofall trans retinoic acid, 13-cis-retinoic acid, CD437, rexinoids, histonedeacetylase inhibitors, DNA methyltransferase inhibitors, hematopoieticgrowth factors, interferon α, interleukin 1, TRAIL, hexamethylenebisacetamide, cholecalciferol, arsenic trioxide, green tea catechinepigallocatechin-3-gallate, DNA topoisomerase II inhibitors, taraxinicacid, verticinone, PPAR-gamma agonists, antibodies versus CD19, CD20 orCD22, CD33-antibodies alone or as conjugate, alkylating cytostatika,purine analogs, cytosine-arabinosides, anticylines, vinca-alkaloids andglucocorticosteroids.
 76. The method according to claim 40, wherein thedifferentiation inducing agent is a histone deacetylase inhibitor. 77.The method according to claim 40, wherein the differentiation inducingagent is all trans retinoic acid.
 78. The method according to claim 40,wherein the agent effective in raising intracellular concentrations ofcAMP is selected from the group consisting of prostaglandin E2,prostacyclin derivatives, dopamine, dobutamine, β2-adrenoreceptoragonists, adenosine A1 receptor agonists, adenosine A2 receptor agonistsand forskolin.
 79. A treatment combination according to claim 62,wherein the differentiation inducing agent is selected from the groupconsisting of all trans retinoic acid, 13-cis-retinoic acid, CD437,rexinoids, histone deacetylase inhibitors, DNA methyltransferaseinhibitors, hematopoietic growth factors, interferon α, interleukin 1,TRAIL, hexamethylene bisacetamide, cholecalciferol, arsenic trioxide,green tea catechin epigallocatechin-3-gallate, DNA topoisomerase IIinhibitors, taraxinic acid, verticinone, PPAR-gamma agonists, antibodiesversus CD19, CD20 or CD22, CD33-antibodies alone or as conjugate,alkylating cytostatika, purine analogs, cytosine-arabinosides,anticylines, vinca-alkaloids and glucocorticosteroids.
 80. A treatmentcombination according to claim 62, wherein the agent effective inraising intracellular concentrations of cAMP is selected from the groupconsisting of prostaglandin E2, prostacyclin derivatives, dopamine,dobutamine, β2-adrenoreceptor agonists, adenosine A1 receptor agonists,adenosine A2 receptor agonists and forskolin.
 81. A treatmentcombination according to claim 62, wherein the differentiation inducingagent is a histone deacetylase inhibitor.
 82. A treatment combinationaccording to claim 62, wherein the differentiation inducing agent is alltrans retinoic acid.
 83. (canceled)
 84. The method according to claim39, wherein the neoplasm of lymphoid cells is leukemia.
 85. Thetreatment combination according to claim 62, wherein the neoplasm oflymphoid cells is leukemia.